This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Studies in HIV-infected humans demonstrate that a 10 fold reduction in plasma viremia reduces the death rate from 50% to 5% and prolongs the survival time from less than 5 years to greater than 10 years. There is a great need to develop a safe and effective HIV/AIDS therapy that requires short-term intervention and long-term control of viral replication. Here, we propose to evaluate the safety and therapeutic potential of in vivo blockade of the inhibitory receptor Programmed Death-1 (PD-1) as a novel therapy to control HIV/AIDS using a SIV/macaque model. We are testing the safety and therapeutic potential of in vivo PD-1 blockade in combination with vaccination in SIV-infected macaques. We hypothesize that combining PD-1 blockade with anti-retroviral therapy (ART) and vaccination will further improve the efficacy of in vivo PD-1 blockade by inducing a robust polyfunctional anti-viral cellular and humoral immunity that is capable of controlling the reemerging viremia following treatment interruption. The vaccine we use is a SIV239 DNA/MVA vaccine and it elicits high frequencies of CD8 and CD4 T cells in uninfected macaques. Blocking Ab is administered prior to or during vaccination. Correlations are conducted to identify immune responses that are critical for viral control. Our goal is to reduce the set point viremia at least by 50-100 fold. If successful, this therapy would potentially improve the health of more than 30 million HIV-infected people across the world. We are yet to start these studies in macaques.